1. Field of Invention
This invention concerns a zero-order sustained release drug delivery system suitable for administration of carbamazepine. In particular, the invention concerns the drug delivery system comprising a polymer matrix made of a hydrophilic polymer or a mixture thereof and a pharmaceutically active agent carbamazepine incorporated into the polymer matrix. The polymer or the polymer mixture forms the matrix for incorporation of a pharmaceutically active agent and participates and is involved in the crystallization process of carbamazepine within the polymer matrix by inhibiting carbamazepine transformation into its dihydrate crystals. Due to a change of anhydrous carbamazepine into an amorphous rather than crystalline form, carbamazepine is released from the polymer matrix in zero-order release rate.
2. Background Art and Related Art Disclosures
Carbamazepine is a well-established antiepileptic compound. It is regarded as a first-line drug in the treatment of patients suffering from partial seizures, with and without second generalization, and in patients with generalized tonic clonic seizures (Porter, R. J., Penry, J. K., pp. 220-231, Advances in Epileptology, Meinardi, H., Rowan, A. J., Eds., Swets & Zeitlinger, Amsterdam (1977) and Acta Neurol. Scand., 64, Suppl. 88 (1981)). Besides being an antiepileptic compound, carbamazepine has also proved effective in the treatment of trigeminal neuralgia and in patients suffering from manic depressive episodes (Neurol. Neurosurg. Psychiat., 29:265-267 (1966); Arch. Neurol., 19:129-136 (1968); Excerpta Medica, 139-147 (1984); and Excerpta Medica, 93-115, (1984)).
Although the half-life of carbamazepine is relatively long, between 25 and 85 hours, after a single dose due to autoinduction, its effect is substantially reduced after repeated dosing (J. Clin. Pharmacol., 23:241-244 (1982); J. Ther. Drug Monit., 3:63-70 (1981); and Europ. J. Clin. Pharmacol., 8:91-96 (1975)). Due to its particular physical properties and due to its increased metabolism, pronounced daily fluctuations in the serum concentration of carbamazepine were observed and are of concern.
Because there is a correlation between peak concentrations of carbamazepine and central nervous system (CNS) side effects, especially in patients receiving polytherapy (Epilepsia, 28:507-514 (1987); Epileysia, 28:286-299 (1987); Epileysia, 21:341-350 (1980); Epilepsia, 25:476-481 (1984) and Arch. Neurol., 41:830-834 (1984)), it is of great clinical importance to assure a steady level of carbamazepine during a 24-hour carbamazepine delivery.
Using conventional carbamazepine formulations, however, this can only be achieved by dividing the total daily intake into several, typically 3-4 doses per day. This is very bothersome for ambulatory patients and laborious for medical personnel in institutions and may, therefore, result in compliance problems.
The availability and introduction of slow release carbamazepine formulations would be, therefore, regarded as a major clinical advantage. To date, such formulation has not been available, mainly due to physical and chemical properties of carbamazepine.
It is well known, that differences due to polymorphism and pseudopolymorphism observed in certain pharmaceuticals are of importance because physical and chemical properties of different crystalline forms of these pharmaceuticals vary. Differences in these chemical or physical properties, such as for example, solubility, can affect their bioavailability and effective clinical use (J. Pharm. Sci., 58:911-929 (1969)).
Several polymorphs of carbamazepine have been identified (Thermomicroscopy in the Analysis of Pharmaceuticals, Pergamon, N.Y., p. 227 (1971); Pharmazie, 11:709-711 (1975). Yakufaku Zasshi, 104:786-792 (1988)), as well as pseudopolymorphs--the dihydrate (Int. J. Pharm., 14:103-112 (1983)); Int. J. Pharm., 20:307-314 (1984)) and an acetone solvate (Pharmacology, 27:85-94 (1983)).
In the presence of water, carbamazepine transforms rapidly to carbamazepine dihydrate. Carbamazepine dihydrate crystals grow by the whisker mechanism (Int. J. Pharm., 20:307-314 (1984)) and conversion has been shown by X-ray powder diffraction to be 95% complete after 1 hour (J. Pharm. Sci., 80:496-500 (1991)).
The inhibition of formation of large crystals of carbamazepine dihydrate are of great importance for its pharmaceutical formulation since the formation of large crystals of carbamazepine dissolve slowly and unpredictably and, therefore, cause bioavailability problems and may result in unpredictable and uncontrollable drug delivery.
Some attempts to overcome the above problems were made. For example, Khanna S. C., et al., U.S. Pat. No. 4,857,336, have described an oral dosage form for administration of carbamazepine wherein a core comprising a paste of a fine carbamazepine powder dissolved in a protective colloid, a hydrophilic swelling agent and, optionally, a water-soluble osmosis inducing-agent was encapsulated in a water-permeable shell impermeable to the components of the core. The water-permeable encapsulation shell permits a water passage through the cell for the transport of the water soluble core components into the surrounding aqueous body fluid. However, in this arrangement the delivered amount is not strictly controllable because it depends on the amount of water present in the surrounding environment, on the permeability of the shell to the water and on the overall kinetics of carbamazepine release from the colloid and its transport through the shell. Additionally, the manufacturing of the paste masses is inconvenient and laborious due to the need for encapsulation and additionally requires use of organic solvents which may affect the drug biological activity.
Another attempt to solve the above problems is described in U.S. Pat. No. 5,284,662, has improved the oral dosage form described above (ibid) by reducing the usage of the organic solvents, particularly in core preparations, thus resulting in somehow easier processing, avoiding possible formation of unsuitable pasty masses in manufacture. However, similarly to above formulation, this formulation does not eliminate or inhibit crystallization and therefore also results in unpredictable drug delivery.
The aim of this invention is to provide a controllable, predictable and true zero-order release dosage formulation of carbamazepine using a simple, fast, easy and more practical manufacturing process than those described in two patents cited above.
The delivery system of the invention comprises carbamazepine formulated as a tablet or other oral formulation based on the matrix of hydrophilic polymers gel layers containing carbamazepine. The polymer matrix inhibits the transformation of anhydrous carbamazepine into crystallized dihydrate resulting in amorphous carbamazepine more readily releasable from the polymer matrix at steady zero-order rate.